Rapamycin (Rapamune®) is an immunosuppressant derived from nature, which has a novel mechanism of action. CCI-779 (rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid) is an ester of rapamycin, which has demonstrated significant inhibitory effects on tumor growth in both in vitro and in vivo models.
Modification of rapamycin has mainly focused on production of its 42-hydroxy ester derivatives. These 42-hydroxy rapamycin ester derivatives are useful for inducing immunosuppression, and in the treatment of transplantation rejection, autoimmune diseases, diseases of inflammation, adult T-cell leukemia/lymphoma, solid tumors, fungal infections, et al.
Esterification of rapamycin at the 42-position has been performed by directly reacting rapamycin with acylating agents. However, as rapamycin contains two secondary hydroxyl groups at positions 31 and 42, attempts to discriminate between these two hydroxyl groups in order to achieve a regioselective synthesis of 42-monoacylated products posed a difficult challenge.
A number of patents involving the synthesis of 42-acylated derivatives have been issued, such as alkyl ester (U.S. Pat. No. 4,316,885), aminoalkyl esters (U.S. Pat. No. 4,650,803), fluorinated esters (U.S. Pat. No. 5,100,883), amide esters (U.S. Pat. No. 5,118,677), carbamate esters (U.S. Pat. No. 5,118,678), alkoxyesters (U.S. Pat. No. 5,233,036), carbonate esters (U.S. Pat. No. 5,260,300), hydroxyesters (U.S. Pat. Nos. 5,362,718 & 6,277,983). However, none of the patents described methods that are stereospecific. Further, the yields for 42-monoesters of rapamycin produced by these methods are typically poor to moderate due to the poor regioselectivity and instability of rapamycin molecule in basic or acidic conditions. High performance liquid chromatography (HPLC) separation is usually required in order to get the pure product. One solution proposed for improving the regioselectivity is the use of 31-silyl protected rapamycin as an intermediate. However, this method adds several more steps of manipulation.
What is needed is an efficient method for synthesis of rapamycin esters.